Hypoxia/reoxygenation caused by ischemia/reperfusion is known to be the main cause of postoperative liver failure associated with liver transplantation and hepatectomy. It is also known that protecting liver sinusoidal endothelial cells (LSECs) is important for the prevention of hepatic disorder caused by ischemia/reperfusion (Caldwell et al. Hepatology, 10, pp. 292 to 299, 1989). Based on a report that hypoxia/reoxygenation causes apoptosis in LSECs (Neal R. Banga et al. J. Surg. Res., 178, pp. e35 to 41, 2012), LSECs are considered to be the major factor in hepatic ischemia-reperfusion injury.
Meanwhile, the sphingolipid mediator sphingosine-1-phosphate (S1P) is produced by the phosphorylation of sphingosine derived from sphingomyelin, a component of the cell membrane, by sphingosine kinase. It exhibits a variety of biological activities via S1P receptors. For example, S1P is known to have anti-apoptotic actions (Cuvillier et al., Nature, 381, pp. 800 to 803, 1996), and also reported to inhibit apoptosis in LSECs in alcoholic liver injury (Dong-Mei Zheng et al. Hepatology, 44, pp. 1278 to 1287, 2006) and renal disorder caused by ischemia/reperfusion (Lee et al. Nephrology, 2011).
From the foregoing viewpoints, there is an expectation for the alleviation of hepatic disorder caused by hypoxia/reoxygenation by protecting LSECs with S1P. However, S1P is a metabolite of sphingolipids, which constitute biomembranes, and present in a large amount in platelets and endothelial cells. This poses a problem that S1P itself cannot be used for the prevention and/or treatment of hepatic ischemia-reperfusion injury by targeting LSECs.
In order to solve this problem, there has been an attempt to alleviate hepatic disorder caused by hypoxia/reoxygenation using the S1P receptor agonist FTY720 (fingolimod hydrochloride: converted to phosphorylated FTY720 in vivo by sphingosine kinase) (American Journal of Transplantation, 5, pp. 40 to 49, 2005). However, there is concern that this compound functions as an S1P antagonist in prolonged administration. Also, although this compound has a chemical structure similar to that of sphingosine as a whole, it is not a direct derivative of S1P for having a phenylene group in its carbon chain. FTY720 is not a compound intended to be used for enabling the application of S1P itself to the protection of LSECs.

Further, in view of reports that hyaluronic acid (HA) accumulates in LSECs after intravascular administration (Fraser J et al. Cell Tissue Res., 242, pp. 505 to 510, 1985) and the hyaluronic acid receptor (HARE/Stabilin-2) is expressed specifically in LSECs (Bin Zhou et al. J. Biol. Chem., 275, pp. 37733 to 37741, 2000), there has been an attempt to efficiently deliver S1P to LSECs by incorporating S1P in hyaluronic acid-coated liposomes (Grants-in-Aid for Scientific Research, Research Subject No: 23390319, “Development of new reagent for liver diseases using S1P and hyaluronic acid”, Nobuhiro Ohkohchi et al., 2011 to 2013). However, there was a problem that hyaluronic acid was functionally deficient as a ligand due to the electric charge, the size of the molecular weight, etc. of the liposomes, resulting in a failure in achieving the desired DDS effect.